Submissions for variant NM_001035.3(RYR2):c.7114C>A (p.Leu2372Ile)

dbSNP: rs765925963

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000182755	SCV000235140	uncertain significance	not provided	2014-08-22	criteria provided, single submitter	clinical testing	p.Leu2372Ile (CTT>ATT): c.7114 C>A in exon 46 of the RYR2 gene (NM_001035.2). A variant of unknown significance has been identified in the RYR2 gene. The L2372I variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The L2372I variant was not observed in approximately 6,000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. However, the L2372I variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Additionally, this substitution occurs at a position that is not conserved across species and in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Furthermore, missense mutations in nearby residues have not been reported indicating this region of the protein may be tolerant of change. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in CARDIOMYOPATHY panel(s).
Invitae	RCV002516884	SCV003469282	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia 1	2022-08-30	criteria provided, single submitter	clinical testing	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 201274). This variant has not been reported in the literature in individuals affected with RYR2-related conditions. This variant is present in population databases (rs765925963, gnomAD 0.007%). This sequence change replaces leucine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 2372 of the RYR2 protein (p.Leu2372Ile).